Harefield Heart Science Centre, Imperial College London, London, UK.
Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK.
Sci Rep. 2018 Oct 23;8(1):15661. doi: 10.1038/s41598-018-33994-8.
Cardiac regeneration post-injury is a tantalizing feature of many lower vertebrates such as fishes and urodeles, but absent in adult humans. Restoration of pumping function is a key endpoint of cardiac regeneration, but very little is known about the biomechanical remodeling process. Here, we quantify and compare the evolution of cellular composition and mechanical stiffness of the zebrafish ventricular myocardium during maturation and following cryoinjury during regeneration to better understand the dynamics of biomechanical remodeling during these two processes. With increasing age, normal myocardial trabecular density and cardiomyocyte fraction increased, while non-myocyte cell fractions decreased. Cell density remained constant during maturation. Cardiomyocyte sarcomeres shortened to a minimum reached at 7.5 months of age, but lengthened with additional age. Concomitantly, ventricular wall stiffness increased up until 7.5 months before plateauing with additional age. Endothelial, myofibroblast/smooth muscle, and cardiomyocyte cell fractions were disrupted following cryoinjury, but were progressively restored to age-specific natural norms by 35 days post infarct (DPI). Infarcted myocardium stiffened immediately following cryoinjury and was a 100-fold greater than non-infarcted tissue by 3 DPI. By 14 DPI, stiffness of the infarcted myocardium had fallen below that of 0 DPI and had completely normalized by 35 DPI. Interestingly, cardiomyocyte sarcomere length increased until 14 DPI, but subsequently shortened to lengths below age-specific natural norms, indicating recovery from a volume overloaded condition. These observations are consistent with the view that regenerating myocardium requires biomechanical stimulation (e.g. strain) to rescue from a volume overloaded condition. Intriguingly, the biomechanical progression of the infarcted adult myocardial wall mirrors that of normal remodeling during aging. The biomechanical progression of the infarcted myocardium targets the values of age-specific norms despite a large divergence in initial conditions. These findings identify a novel biomechanical control of heart regeneration that may orchestrate cellular and tissue level remodeling responses.
心脏在受伤后能够再生，这是鱼类和有尾两栖类等许多低等脊椎动物的诱人特征，但在成年人类中却不存在。恢复心脏的泵血功能是心脏再生的一个关键终点，但人们对其生物力学重塑过程知之甚少。在这里，我们量化并比较了斑马鱼心室心肌在成熟过程中和再生过程中因冷冻损伤而导致的细胞组成和机械硬度的演变，以更好地了解这两个过程中生物力学重塑的动态。随着年龄的增长，正常心肌小梁密度和心肌细胞分数增加，而非心肌细胞分数减少。细胞密度在成熟过程中保持不变。心肌细胞肌节缩短到 7.5 月龄时达到最小，但随着年龄的增加而延长。同时，心室壁硬度增加，直到 7.5 月龄前达到峰值，然后随着年龄的增加而趋于平稳。冷冻损伤后内皮细胞、肌成纤维细胞/平滑肌细胞和心肌细胞的分数被破坏，但在 35 天（DPI）后逐渐恢复到特定年龄的自然正常水平。冷冻损伤后，梗塞心肌立即变硬，在 3 DPI 时比非梗塞组织硬 100 倍。到 14 DPI 时，梗塞心肌的硬度已低于 0 DPI，到 35 DPI 时已完全正常化。有趣的是，心肌细胞肌节长度在 14 DPI 之前增加，但随后缩短至低于特定年龄的自然正常水平，表明从容积超负荷状态中恢复。这些观察结果与以下观点一致，即再生心肌需要生物力学刺激（例如应变）来挽救容积超负荷状态。有趣的是，梗塞成年心肌壁的生物力学进展与衰老过程中的正常重塑相似。尽管初始条件存在很大差异，但梗塞心肌的生物力学进展仍针对特定年龄的正常水平。这些发现确定了心脏再生的一种新的生物力学控制，可能协调细胞和组织水平的重塑反应。
